The blood—brain barrier (BBB) separates the mammalian brain from the systemic circulation and plays a vital role in the homeostasis of the central nervous system (CNS). Despite the continuous progress in understanding transport of peptides through the blood-brain barrier, their efficient delivery directly into the CNS has remained a major challenge in developing neuropeptides as potential therapeutics.
Epilepsy, for example, is a complex neurological disorder. Intractable epilepsy is estimated to affect 30% of the patient population. Despite availability of various antiepileptic drugs (AEDs), certain types of seizures and epilepsy syndromes respond with limited success to only a few AEDs. Therefore, there is an ongoing need to discover and develop new anticonvulsant therapeutics with improved efficacy and safety profiles. Moreover, recent discoveries of neurobiological changes that occur prior to an epileptic seizure have opened an opportunity for the discovery of new antiepileptogenic compounds, and such antiepileptogenic agents can include neuropeptides and neurotrophins.
Neuropeptides and their receptors that have been implicated in the mechanisms of epileptic seizures include galanin, neuropeptide Y, somatostatin and opioid peptides. Some of these neuropeptides, when delivered directly into the central nervous system (CNS), possess an anticonvulsant activity, but their poor bioavailability and marginal metabolic stability preclude development of neuropeptide-based antiepileptic drugs. On the other hand, advanced peptide engineering has produced many successful instances of peptide analogs with improved stability or bioavailability. However, none of the available peptide engineering techniques have been applied to neuropeptides with anticonvulsant activity. What is needed in the art are methods and compositions for improving permeability through the blood-brain barrier.